There was no drug that could simultaneously treat SLE’s unpleasant factors “IFN-I” and “autoantibodies.”

On December 10, Osaka University announced the discovery of a drug that simultaneously focuses on two disease aggravating factors in systemic lupus erythematosus (SLE). This research was carried out by a research group including Atsushi Kumanogo, visiting associate professor Chuta Takamatsu, and visiting faculty member Kenhiro Hirayama from the Department of Respiratory and Immunology at the same university’s Graduate School of Medicine. The research results are published in Arthritis and Rheumatology.

SLE is an autoimmune disease of unknown cause that often occurs in young women, and is characterized by the production of various autoantibodies. It causes damage to important organs such as the brain, lungs, and kidneys, and can be life-threatening if left untreated. Currently, treatment with high doses of steroids and immunosuppressants is performed during the acute exacerbation phase, but serious side effects such as infection, osteoporosis, and diabetes are often considered, and the development of new treatments that are safe and effective for patients is being considered.

It is known that overproduction of type I interferon (IFN-I) and abnormal differentiation and proliferation of B cells are deeply involved in the pathogenesis of SLE. Cell activator inhibitors (such as belimumab) have been developed and are used in some patients.

In this study, we conducted drug screening to address this issue and proposed a new therapeutic strategy that simultaneously controls IFN-I and autoantibody production.

HDAC inhibitor “vorinostat” suppresses IFN-I production and B cell differentiation into plasma cells

In the experiment, they identified the HDAC inhibitor vorinostat by cleaning a compound library and reporter cells that monitor IFN-I activity. Vorinostat reduces IFN-I by targeting TBK1 phosphorylation and IRF3 nuclear translocation. The expression of transcription factors (PRDM1/XBP1/IRF4) essential for plasma cell differentiation decreases, and plasma cell differentiation of B cells is inhibited. A comparison of the action classes of HDAC inhibitors suggested that the main action of vorinostat is mediated by HDAC6, and some involvement of HDAC3 inhibition was also suggested.

Vorinostat improves nephritis and survival rates confirmed in SLE model mice

In validation experiments using SLE model mice such as SAVI and NZB/W F1 mice, vorinostat suppressed the IFN-I gene and reduced autoantibody production, resulting in improved proteinuria and renal pathology, and improved survival rates.

From the above results, HDAC6 inhibition by vorinostat simultaneously suppressed both the type I IFN pathway and the B cell differentiation pathway in SLE, and was equivalent to improving nephritis and extending the survival period of SLE model animals.

New therapeutic approach for SLE, expected to be applied to other autoimmune and inflammatory diseases

This study demonstrates the possibility of controlling both IFN-I and autoantibody production with a single drug as a new approach in the treatment of SLE. Currently approved IFN pathway inhibitors and B cell indicator drugs each inhibit only a single pathway, but vorinostat, which was shown to be effective in this study, is promising in that it can simultaneously inhibit both of these pathological factors.

In addition, since vorinostat is already used as an anticancer drug and has some side effects, it is expected that expanding its indication to SLE (suripositioning) will become a new treatment method that replaces conventional steroid-based treatments.

The research group is interested, saying, “If research advances based on the findings of this study, it may be possible in the future to provide effective treatments not only for SLE but also for other autoimmune and inflammatory diseases that involve overproduction of IFN-I.”(QLife Pro Editorial Department)